Protein kinases constitute a large family of structurally related enzymes that effect the transfer of a phosphate group from a nucleoside triphosphate to a protein acceptor. A vast array of cellular functions, including DNA replication, cell cycle progression, energy metabolism, and cell growth and differentiation, are regulated by reversible protein phosphorylation events mediated by protein kinases. Additionally, protein kinase activity has been implicated in a number of disease states. Accordingly, protein kinase targets have attracted substantial drug discovery efforts in recent years, with several protein kinase inhibitors achieving regulatory approval (reviewed in Fischer, Curr. Med. Chem., 11:1563 (2004); Dancey and Sausville, Nature Rev. Drug Disc., 2:296 (2003)).
PLK is a serine/threonine protein kinase that plays a key role in cell cycle control. PLK controls entry and progression through mitosis at multiple stages by regulating centrosome maturation, activation of initiating factors, degradation of inhibitory components, chromosome condensation, and exit from mitosis (reviewed in Barr et al., Nature Reviews Mol Cell Biol., 5; 429 (2004); Petronczki et al., Dev. Cell, 5; 646 (2008)). PLK has been reported to be overexpressed in numerous cancers such as melanoma, prostate, ovarian, colorectal, pancreatic, non small cell lung, esophageal, endometrial, glioma, squamous cell carcinoma of the head and neck and non-Hodkins lymphoma (Kneisel et al., J Cutan Pathol 29: 354 (2002); Takai et al. Cancer Lett 169: 41 (2001); Takahashi et al Cancer Sci.; 94(2):148 (2003); Macmillan et al, Ann. Surg. Oncol. 8: 729 (2001); Gray et al. Mol. Cancer. Ther. 3: 641 (2004); Dietzmann et al. J. Neurooncol. 53:1 (2001); Ito et al. Br. J. Cancer 90:414 (2005); Weichert et al. Pancreatology. 5:259 (2005); Mito et al. Leuk. Lymphoma 46:225 (2005); Liu et al. Oncology 74:96 (2008); Yamamoto et al. Oncology 70(3):231 (2006); Weichert et al. Cancer Sci. 97(4):271 (2006)). Increased levels of expression are additionally correlated with poor prognosis and survival. (Takai et al. Cancer Lett 164: 41 (2001); Wolf et al. Oncogene 14: 543 (1997); Knecht et al. Cancer Res. 59 (1999); Strebhardt et al. JAMA 283:479 (2000); Weichert et al. World J. Gastroenterol 11:5644 (2005); Tokumitsu et al. Int. J. Oncol. 15: 687 (1999); Takai et al. Cancer Lett. 164:41 (2001); Weichert et al. Prostate 60:240 (2004); Kanaji et al. Oncology 70(2):126 (2006)). Overexpression of the kinase transforms cells, rendering them oncogenic such that they acquire the ability to form tumors in mice (Smith et al., Biochem. Biophys. Res. Commun. 234; 397 (1997)). PLK protein levels are also elevated in tumor relative to normal cell lines in culture. Downregulation of PLK protein expression by RNA interference in tumor cell lines results in a reduction of cell proliferation, mitotic arrest at prometaphase and the rapid progression into apoptosis (Spankuch-Schmitt et al. J Natl. Cancer Inst. 94(24):1863 (2002); Spankuch-Schmitt et al. Oncogene 21(20):3162 (2002)). This effect was not observed in normal cell lines. Moreover downregulation of PLK by short hairpin expression in mice with human xenografts reduced tumor growth to 18% (Spankuch et al. J. Natl. Cancer Inst. 96(11):862 (2004); Kappel et al. Nucleic Acids Res. 34(16) 4527 (2006)). The key role of PLK in mitotic progression, its overexpression in a wide range of malignancies and the anti-proliferative effect observed upon its inhibition demonstrate its feasibility as a therapeutic target.
Accordingly, inhibitors of PLK are useful for treating various diseases or conditions associated with PLK activity, and are especially needed in view of the inadequate treatments currently available for many of these disorders.